The overall goal of this collaborative study between Tufts-New England Medical Center, Boston MA and Christian Medical College, Vellore, India is to investigate the immune response to natural Cryptosporidium spp. infections in children in southern India. Cryptosporidiosis is an important cause of diarrhea in children in developing countries and is the commonest cause of parasitic diarrhea at the study site. The correlates of protective immunity to cryptosporidiosis in humans are poorly understood and there is little information on whether immunity to this parasite is subtype-specific. Knowledge of naturally acquired immunity to specific Cryptosporidium spp. antigens is essential to design strategies to prevent or control disease caused by this parasite. The first specific aim is to investigate the role of immune responses to recombinant (r) antigens rgp15, rp27, rgp900 as well as sporozoite lysate in determining the course of Cryptosporidium infections in children from birth to 3 years of age. We will determine whether immune responses to these antigens are associated with control of infection in primary cryptosporidiosis. We will then determine whether immune responses to these antigens resulting from the primary infection are associated with protection from subsequent infection. The second specific aim is to investigate subtype-specific immune responses to the polymorphic gp40 antigen. We will determine whether repeated episodes of cryptosporidiosis involve the same or different species and subtypes of Cryptosporidium. We will then determine whether immune responses to subtype-specific gp40 are associated with control of the primary infection and whether immune responses to rgp40 1a in children infected with subtype 1a in the primary infection are associated with protection from subsequent homotypic or heterotypic infection. This study is innovative because it will be the first prospective study of subtype- specific immune response in cryptosporidiosis in humans. It is significant because there are no data from longitudinal birth cohort studies that address correlates of protective immunity together with subtype-specific immune responses to this disease in humans. These data will provide the basis for the logical development of interventions, such as appropriate vaccines. PUBLIC HEALTH RELEVANCE: The goal of this collaborative study between Tufts-New England Medical Center, Boston MA and Christian Medical College, Vellore, is to investigate immunity to Cryptosporidium in children in southern India. This parasite is the commonest cause of parasitic diarrhea in this area and there is no vaccine available. Results obtained from this study will be useful for development of vaccines against this parasite.